PROJECT SUMMARY Heart disease is a leading case of mortality and mortality in the United States and is rapidly emerging as a major public health problem in the developing world. The adult heart possesses a limited ability to regenerate and is unable to replace damaged heart muscle after cardiac injury with new cardiac muscle cells. Consequently, fibrosis and scarring are the typical response to injury seen in the adult heart. Nonfunctioning scar tissue does not contribute towards the pumping ability of the heart and over time the increased hemodynamic burden imposed on the heart by the fibrous tissue leads to adverse cardiac remodeling, cardiac dilatation and heart failure. Consequently strategies to inhibit cardiac fibrosis after myocardial infarction hold great promise for preserving cardiac function after myocardial infarction. We demonstrate in this proposal that, intra-cardiac injection of Secreted related frizzled protein 2 (Sfrp2), an extracellular Wnt antagonist, 48 hours after myocardial injury, dramatically decreases cardiac scarring. Although this suggests a role of Wnts as pro- fibrotic molecules, the expression and function of Wnts in the infarcted heart are completely unknown. Wnts are a family of 19 lipophilic proteins that play a crucial role during organogenesis including heart development but the adult uninjured heart minimally expresses Wnts. We provide evidence that several Wnts are re- expressed following injury and expression of Wnt1 is dramatically elevated following cardiac injury and induces cardiac fibroblast proliferation and activation. Cardiac fibroblasts at the infarct site are Wnt responsive and up-regulate downstream mediators of Wnt1 signaling. We further demonstrate that the embryonic heart at sites of fibroblast generation is also Wnt responsive. Considering these observations, we have hypothesized (i) that the adult heart recapitulates a Wnt1 dependent developmental program after cardiac injury to promote cardiac fibrosis and repair and (ii) interruption of Wnt signaling in the cardiac fibroblast will decrease cardiac fibrosis and preserve cardiac function after injury. Our specific aims are to A) To determine whether the injured heart recapitulates a developmental program of Wnt1 expression and response B) To determine downstream targets of Wnt1 that mediate cardiac fibroblast activation and finally C) To determine changes in cardiac function following fibroblast specific interruption of Wnt/2 catenin signaling in the infarcted heart. In summary, our proposed studies using molecular, genetic and physiologic approaches will dissect the role and mechanisms of Wnt1 in regulating cardiac fibrosis in the injured heart. Identification of cell components secreting Wnts, target cells responding to Wnts, and physiological benefits of interrupting Wnt1 signaling in the infarcted heart can potentially lead to novel therapies for myocardial infarction.